Oral clefts are among the most common birth defects, estimated at 1 per 600-700 livebirths worldwide, and in terms of medical care, create a major public health burden for both affected children and their families. As part of the project International Genetic Epidemiology of Oral Clefts (TH Beaty, PI) we conducted a genome wide association study (GWAS) to identify genes influencing risk to oral clefts, either directly, or through interaction with common maternal exposures, using case-parent trios assembled from an international consortium (International Consortium to Identify Genes & Interactions Controlling Oral Clefts). The ongoing analyses and initial results from our GWAS have raised several unanticipated questions. In addition, recent methodological developments (by our group, and others) allow us to regard some of the originally posed questions from novel vantage points, and offer opportunities for more powerful approaches. We therefore propose the development of novel statistical techniques, and to carry additional analyses on maternal exposure and the available genome scan data from more than 2000 complete case-parent trios, to further investigate the genetic and environmental risk factors for oral clefts. In particular, we propose to compare the performance of several publicly available algorithms with the ultimate goal to improve the delineation of de novo copy number variants in the affected oral clefts probands, to carry out comprehensive analyses for gene-gene and gene-environment interactions using novel genome-wide and candidate gene approaches, and to devise a fast and efficient case-parent trio association test for imputed genotypes.